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Abstract

Background: Atherosclerotic lesions are characterized by infiltration of inflammatory cells, for which immunological mechanism may be involved. Furthermore, it has been previously demonstrated that immune system is involved in post-ischemic angiogenesis and that atherosclerosis is associated with enhanced vasa vasorum formation. Both soluble and contact-dependent mediators from T-cells play a crucial role in the development of atherosclerosis. OX40, a membrane-bound molecule of the tumor-necrosis-factor-receptor superfamily, is expressed in activated T-cells, while OX40 ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we examined whether OX40/OX40L system is involved in the pathogenesis of atherosclerosis, especially in terms of vasa vasorum formation.

Method and Results: We first demonstrated that endothelial cells of the deep intima in human coronary atheroma were immunopositive for OX40L (n=5). We then examined whether or not the OX40/OX40L system influences the development of atherosclerosis in apolipoprotein E-deficient (ApoE−/−) mice. ApoE−/− mice and ApoE−/−/OX40L-double-deficient (ApoE−/−/OX40L−/−) mice were fed on a high-fat diet starting at 4 weeks of age. After 8 weeks, aortic en face and aortic root analysis with oil-red O staining demonstrated that the extent of aortic atheroma was significantly less in ApoE−/−/OX40L−/− mice as compared with ApoE−/− mice (9.6±2.2% vs. 13.6±3.5%, P<0.01, 8.1±4.3% vs. 12.7±7.4%, P<0.05, n=16, respectively). To elucidate the role of OX40L in vasa vasorum formation for atherogenesis, we examined adventitial vascularity by immunostaining and confirmed that the number of blood vessels in adventitia was significantly less in ApoE−/−/OX40L−/− mice as compared with ApoE−/− mice (16.0±3.2 vs. 33.5±16.1 vessels/HPF, P<0.01, n=8). Furthermore, capillary formation in implanted matrigel was significantly less in OX40L−/− mice as compared with WT mice.

Conclusions: These results indicate that the OX40/OX40L system plays an important role in neovascularization of atheroma, which may promote the atherosclerotic process, suggesting that the OX40/OX40L system could be a new therapeutic target for the treatment of atherosclerosis.